Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling

• Published in: Circulation (New York, N.Y.) Vol. 104; no. 16; pp. 1899 - 1904
• Main Authors: Herman, M P, Sukhova, G K, Libby, P, Gerdes, N, Tang, N, Horton, D B, Kilbride, M, Breitbart, R E, Chun, M, Schönbeck, U
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 16.10.2001
• Subjects: Aorta - enzymology; Aorta - pathology; Arteriosclerosis - enzymology; Arteriosclerosis - pathology; Carotid Arteries - enzymology; Carotid Arteries - pathology; CD40 Ligand; Cells, Cultured; Collagen - metabolism; Cytokines - pharmacology; Endothelium, Vascular - enzymology; Endothelium, Vascular - pathology; Gene Expression Profiling; Humans; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - enzymology; Matrix Metalloproteinase 8 - biosynthesis; Matrix Metalloproteinase 8 - genetics; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - pathology; Phagocytes - enzymology; Phagocytes - pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/hc4101.097419

Loss of interstitial collagen, particularly type I collagen, the major load-bearing molecule of atherosclerotic plaques, renders atheroma prone to rupture. Initiation of collagen breakdown requires interstitial collagenases, a matrix metalloproteinase (MMP) subfamily consisting of MMP-1, MMP-8, and MMP-13. Previous work demonstrated the overexpression of MMP-1 and MMP-13 in human atheroma. However, no study has yet evaluated the expression of MMP-8, known as "neutrophil collagenase," the enzyme that preferentially degrades type I collagen, because granulocytes do not localize in plaques. Transcriptional profiling and reverse transcription-polymerase chain reaction analysis revealed inducible expression of MMP-8 transcripts in CD40 ligand-stimulated mononuclear phagocytes. Western blot analysis demonstrated that 3 atheroma-associated cell types, namely, endothelial cells, smooth muscle cells, and mononuclear phagocytes, expressed MMP-8 in vitro upon stimulation with proinflammatory cytokines such as interleukin-1beta, tumor necrosis factor-alpha, or CD40 ligand. MMP-8 protein elaborated from these atheroma-associated cell types migrated as 2 immunoreactive bands, corresponding to the molecular weights of the zymogen and the active molecule. Extracts from atherosclerotic, but not nondiseased arterial tissue, contained similar immunoreactive bands. Moreover, all 3 cell types expressed MMP-8 mRNA and protein in human atheroma in situ. Notably, MMP-8 colocalized with cleaved but not intact type I collagen within the shoulder region of the plaque, a frequent site of rupture. These data point to MMP-8 as a previously unsuspected participant in collagen breakdown, an important determinant of the vulnerability of human atheroma.